The pathogenesis of insulin requiring diabetes in man has been shown to have genetic (largely HLA associated) and auto-immune components, however the nature and timing of the causative events in the disease remains uncertain. In these proposals we undertake to utilize mouse models to explore chemical toxins to pancreatic beta cells as related to subsequent beta cell necrosis, inflammation of the islets and the diabetes state. In studies to date, we have shown that single "sub diabetogenic" doses of streptozotocin (SZ) in various strains of mice induce delayed onset hyperglycemia and inflammation of the islets over time. Sensitivity to the drug is increased in younger animals and in male versus female mice. Testosterone in vivo or in vitro augments the beta cell toxicity from SZ. These observations recall the early age of onset and the male to female preponderance of insulin requiring diabetes in man. The human incidence peak in early adolescence may also now have significance. We have completed experiments to test the reports of Buschard and colleagues of human to nude mice transfer of diabetes by lymphocyte injections with totally negative results. Thus to our mind, immunological transfer of diabetes to animals has yet to be convincingly shown. We plan to extend our studies to examine the effects of alloxan, L-asparaginase and Vacor on mice in parallel with SZ, and to test whether the determinants of age and sex are similar for these drugs as we have shown for SZ. We will also reexamine the delayed onset hyperglycemia model following chemical beta cell injury, to see what role immunological sensitization of the mice to their islet cells plays in the degree of beta cell destruction seen. Maneuvers planned include immunological transfer between inbred mice, immunological suppression and a systematic pathological examination of the pancreases of mice treated with the above chemical agents. Islet cell antibodies will also be sought. With few modifications, our aims remain essentially as in the original application.